Abstract
Squamous cell carcinoma of the head and neck (SCCHN) is a common, aggressive, treatment-resistant cancer with a high recurrence rate and mortality, but the mechanism of treatment resistance remains unclear. Here we describe a mechanism where the AAA-ATPase TRIP13 promotes treatment resistance. Overexpression of TRIP13 in non-malignant cells results in malignant transformation. High expression of TRIP13 in SCCHN leads to aggressive, treatment-resistant tumors and enhanced repair of DNA damage. Using mass spectrometry, we identify DNA-PKcs complex proteins that mediate nonhomologous end joining (NHEJ), as TRIP13-binding partners. Using repair-deficient reporter systems, we show that TRIP13 promotes NHEJ, even when homologous recombination is intact. Importantly, overexpression of TRIP13 sensitizes SCCHN to an inhibitor of DNA-PKcs. Thus, this study defines a new mechanism of treatment resistance in SCCHN and underscores the importance of targeting NHEJ to overcome treatment failure in SCCHN and potentially in other cancers that overexpress TRIP13.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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ATPases Associated with Diverse Cellular Activities
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Animals
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Antineoplastic Agents / pharmacology
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Carcinoma, Squamous Cell / drug therapy
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Carcinoma, Squamous Cell / genetics*
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Carcinoma, Squamous Cell / metabolism
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Carcinoma, Squamous Cell / pathology
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Carrier Proteins / antagonists & inhibitors
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Carrier Proteins / genetics*
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Carrier Proteins / metabolism
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Cell Cycle Proteins
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Cell Line, Transformed
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Cell Line, Tumor
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Cell Movement
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism
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Cell Transformation, Neoplastic / pathology
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Chick Embryo
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Chorioallantoic Membrane / blood supply
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Chorioallantoic Membrane / drug effects
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Chorioallantoic Membrane / metabolism
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DNA Breaks, Double-Stranded
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DNA End-Joining Repair*
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DNA-Activated Protein Kinase / antagonists & inhibitors
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DNA-Activated Protein Kinase / genetics*
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DNA-Activated Protein Kinase / metabolism
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Drug Resistance, Neoplasm / genetics
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Gene Expression Regulation, Neoplastic*
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Head and Neck Neoplasms / drug therapy
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Head and Neck Neoplasms / genetics*
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Head and Neck Neoplasms / metabolism
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Head and Neck Neoplasms / pathology
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Humans
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Injections, Subcutaneous
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Keratinocytes / drug effects
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Keratinocytes / metabolism
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Keratinocytes / pathology
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Mice
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Mice, Nude
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NIH 3T3 Cells
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Nuclear Proteins / antagonists & inhibitors
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Nuclear Proteins / genetics*
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Nuclear Proteins / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Signal Transduction
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Squamous Cell Carcinoma of Head and Neck
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Carrier Proteins
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Cell Cycle Proteins
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Nuclear Proteins
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RNA, Small Interfering
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DNA-Activated Protein Kinase
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PRKDC protein, human
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ATPases Associated with Diverse Cellular Activities
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TRIP13 protein, human